| Dysregulation of telomerase activity and expression in lymphokine-activated killer cells from advanced cancer patients: possible involvement in cancer-associated immunosuppression mechanism. | |
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MedLine Citation:
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PMID: 11295096 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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There exists cancer-associated immunosuppression, and the generation of lymphokine-activated killer (LAK) cells is impaired in patients with advanced cancer. Telomerase has been reported to be upregulated in the activation of lymphocytes to proliferate against immune stimulation as well as in the malignant transformation of immortal cancer cells. We attempted to clarify the involvement of telomerase in the impairment of LAK cell generation in patients with advanced cancer. LAK cells were generated by stimulation with interleukin (IL)-2 and immobilized anti-CD3 antibody (IL-2/CD3 system) from peripheral blood mononuclear cells of healthy volunteers (he-LAK) or patients with advanced cancer (ca-LAK), and proliferative potential of LAK cells was evaluated on the basis of population doubling level (PDL). Telomere length and telomerase activity of LAK cells were measured by the hybridization with oligonucleotide (TTAGGG)4 and by the telomeric repeat amplification protocol (TRAP) assay, respectively. Effects on telomerase activity in LAK cells of serum from cancer patients, transforming growth factor (TGF)-beta, and IL-10 were also examined. The lifespan of ca-LAK (15.2 +/- 5.1 PDLs) was significantly shorter than that of he-LAK (22.6 +/- 8.3 PDLs) (p = 0.0358). There were no significant differences between he- and ca-LAK in telomere length before IL-2/CD3 stimulation and maximal telomerase activity induced. The telomerase activity induced in ca-LAK failed to elongate sufficiently the telomeric ends (-35.2 +/- 46.2 bp) compared with that in he-LAK (16.8 +/- 41.5 bp) (p = 0.0448). The telomerase activity was initially detectable on day 2 in all he-LAK, whereas 8 (61.5%) of 13 ca-LAK expressed telomerase activity on day 3 or later following the stimulation, showing a significant retardation of telomerase expression (p = 0.0116). The addition to the LAK cell generation system of serum from cancer patients, as well as IL-10, but not transforming growth factor (TGF)-beta, suppressed the telomerase activity. This serum-induced suppression of telomerase activity in LAK cells was abrogated with the addition of anti-IL-10 antibody but not with anti-TGF-beta antibody. It is suggested that the dysregulation of telomerase activity and expression exists in LAK cells of cancer patients, resulting in the impairment of LAK cell generation in patients with advanced cancer. Serum IL-10 may be involved in the impairment of LAK cell generation by the suppression of telomerase activity of lymphocytes in vivo. Thus, the dysregulation mechanism of telomerase activity and expression in lymphocytes of cancer patients may be attributable, in part, to cancer-associated immunosuppression. |
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Authors:
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K Minami; Y Yamaguchi; K Yoshida; C P Quan; T Toge |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Oncology reports Volume: 8 ISSN: 1021-335X ISO Abbreviation: Oncol. Rep. Publication Date: 2001 May-Jun |
Date Detail:
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Created Date: 2001-04-11 Completed Date: 2001-07-05 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 9422756 Medline TA: Oncol Rep Country: Greece |
Other Details:
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Languages: eng Pagination: 649-53 Citation Subset: IM |
Affiliation:
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Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Minami-ku, Hiroshima 734-8553, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Aged Aged, 80 and over Female Humans Immune Tolerance Interleukin-10 / metabolism Killer Cells, Lymphokine-Activated / enzymology* Lymphocyte Activation Male Middle Aged Neoplasms / enzymology* Telomerase / metabolism* Telomere / metabolism* Transforming Growth Factor beta / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Transforming Growth Factor beta; 130068-27-8/Interleukin-10; EC 2.7.7.49/Telomerase |
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